Niraparib PBPK modeling to predict optimal dosage in patients with hepatic impairment

To develop a physiologically based pharmacokinetic (PBPK) model of niraparib, predictive of optimal dosage in patients with hepatic impairment and of key pharmacological factors of toxicity.

A comprehensive systematic literature review was conducted in PubMed and ClinicalTrials.gov, to gather all sources reporting niraparib PK data, in accordance with PRISMA guidelines. The PBPK model of niraparib was built using the PK-Sim® software (version 12.1). Parameter calibration was performed using an Approximate Bayesian Computation Sequential Monte Carlo (ABC-SMC) approach, which was implemented in R (version 4.0.2). Model development, analysis, validation, and forward simulations were performed using the Open Systems Pharmacology (OSP) suite (version 12.3.1) in R.

Five drug-specific parameters (LogP, pKa, intestinal permeability, renal clearance, and carboxylesterase 1 (CES1) metabolism specific clearance (CL_spec)) were optimized to reproduce plasma concentration-time profiles across dose levels, consistent with mass balance data. Validation against independent datasets confirmed model performance. Hepatic impairment was defined by NCI-ODWG criteria, with CES1 CL_spec modeled as a power function of total bilirubin (TBIL) in plasma, to capture impaired clearance. PK simulations under a 300 mg QD regimen across four hepatic impairment groups categorized by μM values of TBIL (mild, moderate, severe60, severe120) demonstrated an increase in steady-state niraparib total concentration in plasma AUCs vs. the predicted normal value of 4155 μM·min, by 33%, 57%, 71% and 101%. Upon dose adjustments to 250 mg for mild, 200 mg for moderate, and 150 mg for the severe60 and severe120 categories, simulations predicted mean AUCs which remained within a ±20% range for all compartments, as compared to patients with normal hepatic function receiving the full dose of 300 mg. A sensitivity analysis showed that pKa and CL_spec were the strongest determinants of exposure in the tissue intracellular compartments.

The PBPK model reliably reproduced clinical pharmacokinetics, supported dose adjustment strategies for hepatic impairment, and provides a framework for exploring niraparib safety and further dosing in special populations.